The chemical composition of Persistent Organic Pollutants (POPs) in the environment is not uniform throughout the world, and these contaminants contain many structurally different lipophilic compounds. In a well-defined study cohort in the Slovak Republic, the POP chemicals present in the peripheral blood of exposed children were chemically analyzed. The chemical analysis data revealed that the relative concentration and profile of structurally different organic pollutants, including polychlorinated biphenyls (PCBs), 2,2’-bis(4-chlorophenyl)-1,1- dichloroethylene (p,p’-DDE), 2,2’-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p’-DDT), hexachlorobenzene (HCB) and β-hexachlorocyclohexane (β-HCH), may vary from individual to individual, even within the same exposure area. These chemicals can be broadly classified into two groups. The first group, the PCB congeners, primarily originated from industrial compounds and their byproducts. The second group of compounds originated from or was commonly used in the agricultural sector (e.g., DDT, HCB). The objective of this study was to examine the effects of the two POP exposure profiles on gene expression. For the study population, we selected prepubertal girls (mean age of 46.2 ± 1.4 months) with high POP concentrations in their blood (> 75% tile of total POP) and classified them in the high ‘PCB’ group when the total PCB concentration was significantly higher than the total concentration of other POP components and in the ‘Other Than PCB’ (OTP) group, when the total PCB concentration was significantly lower than the concentration of the other major POP constituents. A matched control group of girls (< 25% tile of total POP) was selected for comparison purpose (n = 5 per group). Our aims were to determine whether there were any common effects of high POP exposure at a toxicogenomic level and to investigate how exposure may affect physiological functions of the children in two different exposure scenarios. Global gene expression analysis using a microarray (Affymetrix Gene Chip Human genome U133 Plus 2.0 Array) platform was conducted on the total RNA of peripheral blood mononuclear cells from the girls. The results were analyzed by Partek GS, Louis, MI, which identified twelve genes (ATAD2B, BIVM, CD96, CXorf39, CYTH1 ETNK1, FAM13A, HIRA, INO80B, ODG1, RAD23B, and TSGA14) and two unidentified probe sets, as regulated differentially in both the PCB and OTP groups against the control group. The qRT-PCR method was used to validate the microarray results. The Ingenuity Pathway Analysis (IPA) software package identified the possible molecular impairments and disease risks associated with each gene set. Connective tissue disorders, genetic disorders, skeletal muscular disorders and neurological diseases were associated with the 12 common genes. The data therefore identified the potential molecular effects of POP exposure on a genomic level. This report underscores the importance of further study to validate the results in a random population and to evaluate the use of the identified genes as biomarkers for POP exposure.